Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells.
Urokinase-type plasminogen activator (uPA) signaling via its receptor uPAR inhibits late events in HIV-1 replication in acutely infected primary monocyte-derived macrophages (MDMs) and promonocytic U937 cells. Here we show that U937-derived, chronically infected U1 cells stimulated with phorbol 12-myristate 13-acetate (PMA) express integrins, uPA, and soluble uPAR at levels similar to those of MDMs. uPA inhibited HIV expression in U1 cells incubated with either PMA or tumor necrosis factor-alpha (TNF-alpha), but not with other HIV-inductive cytokines or lipopolysaccharide. Of interest, only PMA and TNF-alpha, but not other HIV-inductive stimuli, induced surface expression of the alpha(M) chain CD11b in U1 cells constitutively expressing CD18, the beta(2) chain of the Mac-1 integrin. Like uPA, fibrinogen, a Mac-1 (CD11b/CD18) ligand, and M25, a peptide homologous to a portion of the beta-propeller region of CD11b preventing its association with uPAR, inhibited HIV virion release in PMA-stimulated U1 cells. Both uPAR small-interference RNA (siRNA) and soluble anti-beta(1)/-beta(2) monoclonal antibodies abolished the anti-HIV effects of uPA, whereas CD11b siRNA reversed the anti-HIV effect of M25, but not that induced by uPA. Thus, either uPA/uPAR interaction, Mac-1 activation, or prevention of its association with uPAR triggers a signaling pathway leading to the inefficient release of HIV from monocytic cells.
Alfano
Massimo
M
AIDS Immunopathogenesis Unit, San Raffaele Scientific Institute, Milan, Italy. alfano.massimo@hsr.it
Mariani
Samanta A
SA
Elia
Chiara
C
Pardi
Ruggero
R
Blasi
Francesco
F
Poli
Guido
G
D051696:Activating Transcription Factors / Q000494:pharmacology; D001798:Blood Proteins / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000821:virology; D009000:Monocytes / Q000166:cytology / Q000821:virology*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D051696:Activating Transcription Factors; D001798:Blood Proteins; D039481:CD11b Antigen; D018821:CD18 Antigens; D002273:Carcinogens; C509295:ITGAM protein, human; D039641:Integrin beta Chains; D008024:Ligands; D016177:Macrophage-1 Antigen; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha; D014568:Urokinase-Type Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate